Methorexate is a prototype of an antimetabolite agent. The biochemical formulae below easily explain the role of methotrexate which is a competitive inhibitor of folic acid for the enzyme dihydrofolate reductase.
Once inside the cell, methotrexate undergoes successive glutamylations by adding glutamate radicals after the already existing glutamate, increasing the molecule’s negative charge, thus increasing its intracellular concentration by inhibiting the efflux out of the cell.
This polyglutamylation is related to an enzyme called folypolyglutamate synthetase which can add up to 4 to 8 glutamate radicals.
Polyglutamyled methotrexate can bind with the same affinity to the dihydrofolate enzyme as the original methotrexate, but the bind is more stable, thus reinforcing its action.
Commonly used dosage
- Choriocarcinoma
- Mammary and ovarian adenocarcinoma: adjuvant or initial treatment
- Head and neck cancers
- Small cell lung cancer
- Acute lymphocytic leukaemia as maintenance treatment
High dosage
- Childhood acute lymphocytic leukaemia
- maintenance treatment
- prophylaxis of spreading to central nervous system
- Non-Hodgkin's lymphoma
- Osteosarcoma
Only specific toxicities (or major toxicities) are described here. Other common chemotherapy toxicities are described in the chapter on chemotherapy toxicity.
Haematological toxicity
Haematological toxicity is a constant drawback of high dose chemotherapy.
It generally begins with thrombopaenia, rapidly followed by neutropaenia which is very intense.
Repeated haemograms should therefore be prescribed for these dosages.
Renal toxicity
Renal toxicity is in the form of tubular necrosis with precipitation of methotrexate cristals (when using high dosage).
Urine should therefore always be alkaline.
From a simple elevation of serum creatinine, such renal toxicity can develop towards irreversible renal insufficiency.
Mouth ulcerations
These superficial mouth ulcerations are very painful and should be treated by local and general analgesics and antiseptics.
The superficial skin ulcerations can lead to generalised erythrodermia followed by skin ulcerations.
Mucous ulcerations are also observed along the entire digestive tract.
Pulmonary toxicity
There are immunoallergic pneumopathies which require early, intense corticosteroid treatment. Treatment by methotrexate should therefore never be re-introduced. Such methotrexate induced pneumopathies should therefore be clearly distinguished from more frequent infectious diseases.
Neurological toxicity
This toxicity is observed when methotexate is used by intrathecal administration or when high dosage is used. The symptoms may be coma, confusion, ataxia, paraplegia or dyskinetic movements. Generally, these symptoms disappear without sequelae (except if simultaneous irradiation is performed on CNS).
At least two different situations can be described:
low dosage
Treatment with 30 to 50 mg/m2 every 3 to 4 weeks,
This dosage is used for choriocarcinoma (weekly injections) and other epithelioma
high dosage
The dosage is usually 8 to 12 g/m2 and necessitates very intense hydration, a regular serum measurement of methotrexate and adjustment of folinic acid perfusion in relation to results. It is therefore a very specific and potentially perilous treatment in inexperienced hands.
Methotrexate is a specific inhibitor of dihydrofolate reductase. The antidote is folinic acid which should be administrated providing precise monitoring of circulating methotrexate level, and should also be adapted according to the renal and liver functions with hyperhydration and alkalinisation of urine.
This treatment should only be administered in very well trained cancer units.